Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated homocysteine levels have been associated with arteriosclerosis and thrombosis. Hyperhomocysteinemia is caused by altered functioning of enzymes of its metabolism due to either inherited or acquired factors. Betaine-homocysteine methyltransferase (BHMT) serves, next to methionine synthase, as a facilitator of methyl group donation for remethylation of homocysteine into methionine, and reduced functioning of BHMT could theoretically result in elevated homocysteine levels. Recently, the genomic sequence of the BHMT gene was published. Mutation analysis may reveal mutations of the BHMT gene that could lead to hyperhomocysteinemia. In the present study we performed genomic sequencing of the BHMT gene of 16 vascular patients with hyperhomocysteinemia and detected three mutations in the coding region of this gene. The first was an amino acid substitution of glycine to serine (G199S), which was found only in the heterozygous state. The second mutation was a substitution of glutamine to arginine (Q239R), and the last mutation was an amino acid substitution of glutamine to histidine (Q406H). The latter was also found only in the heterozygous state. The relevance of these mutations was tested in a study group, which consists of 190 cases with vascular disease and 601 controls. The influence of these three mutations on homocysteine levels was investigated. None of the three mutations led to significantly changed homocysteine levels. In addition, no differences in genotype distribution between cases and controls were found. So far, our results provide no evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease.
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PMID:Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans. 1107 19

Hyperglycemia leads to vascular disease specific to diabetes mellitus. This pathology, which results from abnormal proliferation of smooth muscle cells in arterial walls, may lead to cataract, renal failure, and atherosclerosis. The hexosamine biosynthetic pathway is exquisitely responsive to glucose concentration and plays an important role in glucose-induced insulin resistance. UDP-GlcNAc: polypeptide O-N-acetylglucosaminyltransferase (O-GlcNAc transferase; OGTase) catalyzes the O-linked attachment of single GlcNAc moieties to serine and threonine residues on many cytosolic or nuclear proteins. Polyclonal antibody against OGTase was used to examine the expression of OGTase in rat aorta and aortic smooth muscle (RASM) cells. OGTase enzymatic activity and expression at the mRNA and protein levels were determined in RASM cells cultured at normal (5 mM) and at high (20 mM) glucose concentrations. OGTase mRNA and protein are expressed in both endothelial cells and smooth muscle cells in the aorta of normal rats. In both cell types, the nucleus is intensely stained, while the cytoplasm stains diffusely. Immunoelectron microscopy shows that OGTase is localized to euchromatin and around the myofilaments of smooth muscle cells. In RASM cells grown in 5 mM glucose, OGTase is also located mainly in the nucleus. Hyperglycemic RASM cells also display a relative increase in OGTase's p78 subunit and an overall increase protein and activity for OGTase. Biochemical analyses show that hyperglycemia qualitatively and quantitatively alters the glycosylation or expression of many O-GlcNAc-modified proteins in the nucleus. These results suggest that the abnormal O-GlcNAc modification of intracellular proteins may be involved in glucose toxicity to vascular tissues.
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PMID:Hyperglycemia and the O-GlcNAc transferase in rat aortic smooth muscle cells: elevated expression and altered patterns of O-GlcNAcylation. 1133 5

E-selectin mediates the rolling of circulating leukocytes on vascular endothelial cells. A polymorphism, in which serine is substituted for arginine at position 128 (S128R) in the EGF domain, has been associated with both early-onset atherosclerosis and SLE. We investigated whether the substitution alters the ligand-binding properties of E-selectin under shear flow by studying the capacity of Chinese hamster ovary cell transfectants expressing wild type (WT) or S128R E-selectin to support interactions of neutrophils, K562 cells or HL60 cells. We initially chose to study non-fucosylated K562 cells. No interactions were observed on WT E-selectin, whereas S128R supported a transient tethering interaction of K562 cells, which was resistant to digestion with either neuraminidase or O-sialoglycoprotein endopeptidase, and, in turn, could result in firm adhesion in the presence of a beta2-integrin. HL60 cells exhibited increased rolling on S128R E-selectin. Although neuraminidase treatment inhibited all HL60 interactions with WT E-selectin, it unmasked transient tethers on S128R. We further observed that S128R recruited significantly more neutrophils than WT E-selectin, without affecting neutrophil rolling velocity. This polymorphism may therefore amplify leukocyte-endothelial cell interactions and may be a factor linking the S128R polymorphism to vascular disease.
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PMID:The S128R polymorphism of E-selectin mediates neuraminidase-resistant tethering of myeloid cells under shear flow. 1178 16

Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners. A fragment containing the N-terminal 272 amino acid residues of KRIT1, a region lacking similarity to any known protein upon database searches, was used as bait. From parallel screens of human fetal brain and HeLa cDNA libraries, we obtained multiple independent isolates of human integrin cytoplasmic domain-associated protein-1 (ICAP-1) as interacting clones. The interaction of KRIT1 and ICAP-1 was confirmed by GST-KRIT1 trapping of endogenous ICAP-1 from 293T cells. The alpha isoform of ICAP-1 is a 200 amino acid serine/threonine-rich phosphoprotein which binds the cytoplasmic tail of beta1 integrins. We show that mutagenesis of the N-terminal KRIT1 NPXY amino acid sequence, a motif critical for ICAP-1 binding to beta1 integrin molecules, completely abrogates the KRIT1/ICAP-1 interaction. The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton. Furthermore, these data suggest that KRIT1 might affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.
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PMID:KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. 1185 71

The recent discovery of an ATP-binding cassette transporter, ABCA1, as an important regulator of high density lipoprotein (HDL) metabolism and reverse cholesterol transport has facilitated the identification of novel variants associated with HDL cholesterol deficiency states. We identified a subject with HDL cholesterol deficiency (4 mg/dl) who developed and died of complications related to cerebral amyloid angiopathy (CAA). The proband had a compound heterozygous mutation. One mutation was a G3295T substitution with conversion of asparagine to tyrosine (D1099Y) in ABCA1. The single-base substitution at codon 1099 resulted in the abolition of an RsaI cleavage site. The proband and affected individuals having another mutation were heterozygotes for T5966C with phenylalanine converted to serine (F2009S). The presence of the T5966C mutation was detected by restriction digestion with HinfI. These variants were not identified in over 400 chromosomes of healthy subjects. In the kindred, family members heterozygous for the ABCA1 variant exhibited low levels of HDL cholesterol. Direct sequencing of all coding regions and splice site junctions of other HDL candidate genes revealed no additional mutations, indicating that combined defective ABCA1 alleles may result in familial HDL deficiency.
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PMID:Novel ABCA1 compound variant associated with HDL cholesterol deficiency. 1200 25

E-selectin is a cytokine-inducible endothelial cell adhesion molecule that binds a restricted population of T lymphocytes consisting of Th1 memory cells bearing the cutaneous lymphocyte Ag (CLA). A serine to arginine (S128R) polymorphism in E-selectin has been reported at increased frequency in patients with systemic lupus erythematosus and atherosclerosis. Here we tested the hypothesis that the S128R substitution may contribute to increased vascular disease by altering the number and/or phenotype of lymphocytes interacting with E-selectin under shear flow. We observed that CHO cell monolayers transfected with S128R recruited significantly greater numbers of unfractionated lymphocytes than monolayers expressing an equivalent density of wild-type (WT) E-selectin. Depletion of the CLA(+) subpopulation or generation of CLA(-) lymphoblasts abolished rolling and arrest on WT E-selectin, but left a residual population that interacted with S128R. Generation of Th subsets revealed preferential interaction of Th0 and Th2, but not Th1, cells with S128R compared with WT. However, only T cells of a memory phenotype interacted with S128R, since neither monolayer supported rolling of CD45RA(+) cells. Our results demonstrate that the S128R polymorphism extends the range of lymphocytes recruited by E-selectin, which may provide a mechanistic link between this polymorphism and vascular inflammatory disease.
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PMID:Enhanced recruitment of Th2 and CLA-negative lymphocytes by the S128R polymorphism of E-selectin. 1242 68

Cigarette smoking produces pulmonary hypertension (PHT) through unknown mechanisms. In animal models acute smoke exposure induces cell proliferation in the small arteries adjacent to the alveolar ducts, and chronic exposure results in muscularisation of these vessels, with changes related to the development of PHT. Studies indicate that serine-elastase inhibitors can prevent experimental monocrotaline-induced PHT. This study examined whether they could also prevent cigarette smoke-induced pulmonary vascular disease. Guinea-pigs were exposed to cigarette smoke or air for 6 months. Some animals also received ZD0892, an orally active, synthetic, selective, serine-elastase inhibitor. The percentage of muscularised, small, pulmonary arteries was determined by morphometric analysis of histological sections and vascular cell proliferation by proliferating cell nuclear antigen staining. Vascular cell proliferation was markedly increased in the smoke-exposed animals and the percentage of completely muscularised small vessels was increased four-fold. Cell proliferation indices correlated with muscularisation indices. In the animals treated with ZD0892, the number of completely muscularised vessels was reduced by 50% and cell proliferation was reduced by 61%. These data suggest that smoke-induced cell proliferation leads to pulmonary arterial muscularisation. Serine-elastase inhibitors appear to be able to reduce cell proliferation and vascular remodelling.
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PMID:A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels. 1288 54

Advanced glycation end products (AGEs) derived from glucose are implicated in the pathogenesis of diabetic vascular disease. However, many lines of evidence suggest that other pathways also promote AGE formation. One potential mechanism involves oxidants produced by the NADPH oxidase of neutrophils, monocytes, and macrophages. In vitro studies have demonstrated that glycolaldehyde, a product of serine oxidation, reacts with proteins to form N(epsilon)-(carboxymethyl)lysine (CML), a chemically well-characterized AGE. We used mice deficient in phagocyte NADPH oxidase (gp91-phox(-/-)) to explore the role of oxidants in AGE production in isolated neutrophils and intact animals. Activated neutrophils harvested from wild-type mice generated CML on ribonuclease A (RNase A), a model protein, by a pathway that required L-serine. CML formation by gp91-phox(-/-) neutrophils was impaired, suggesting that oxidants produced by phagocyte NADPH oxidase contribute to the cellular formation of AGEs. To determine whether these observations are physiologically relevant, we used isotope-dilution gas chromatography/mass spectrometry to quantify levels of protein-bound CML in mice suffering from acute peritoneal inflammation. Phagocytes from the gp91-phox(-/-) mice contained much lower levels of CML than those from the wild-type mice. Therefore, oxidants generated by phagocyte NADPH oxidase may play a role in AGE formation in vivo by a glucose-independent pathway.
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PMID:Production of N(epsilon)-(carboxymethyl)lysine is impaired in mice deficient in NADPH oxidase: a role for phagocyte-derived oxidants in the formation of advanced glycation end products during inflammation. 1288 33

Obesity is commonly associated with elevated plasma levels of free fatty acids (FFAs). High levels of FFA have emerged as a major link between obesity and insulin resistance/type 2 diabetes (T2DM). Thus, acute and chronic elevations of plasma FFAs produce insulin resistance in skeletal muscle and liver. In skeletal muscle, FFA-induced insulin resistance is associated with accumulation of intramyocellular triglyceride and diacylglycerol, and with activation of protein kinase C (the beta and delta isoforms). It is suggested that FFAs interfere with insulin signalling via PKC-induced serine phosphorylation of the insulin receptor substrate-1. In the liver, FFAs cause insulin resistance by interfering with insulin suppression of glycogenolysis. In beta-cells, FFAs potentiate glucose-stimulated insulin secretion acutely and chronically. It is postulated that this prevents the development of T2DM in most (>80%) obese insulin-resistant people who have FFA-mediated insulin resistance. Elevated levels of FFA also seem to activate a pro-inflammatory and pro-atherogenic pathway (the IkappaB/NFkappaB pathway) and may be responsible, at least in part, for the increase in atherosclerotic vascular disease seen in patients with T2DM. As increased plasma levels account for up to 50% of insulin resistance in obese patients with T2DM, lowering of plasma FFAs could be a new and promising approach to the treatment of T2DM.
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PMID:Nutritional effects of fat on carbohydrate metabolism. 1296 93

Elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Cystathionine beta-synthase (CBS) is an enzyme that condenses homocysteine with serine to form cystathionine. In this article, we describe the effects of modulating CBS activity using a transgenic mouse that contains the human CBS cDNA under control of the zinc-inducible metallothionein promoter (Tg-CBS). In the presence of zinc, Tg-CBS mice have a 2- to 4-fold increase in liver and kidney CBS activity compared with nontransgenic littermates. Transgenic mice on standard mouse chow had a 45% decrease in their serum homocysteine (12.1 to 7.2 micromol/L; P<0.0001) when zinc was added to drinking water, although zinc had minimal effect on their nontransgenic siblings (13.2 micromol/L versus 13.0 micromol/L; P=NS). Tg-CBS mice maintained on a high-methionine, low-folate diet also had significantly lower serum homocysteine compared with control animals (179 micromol/L versus 242 micromol/L; P<0.02). CBS overexpression also significantly lowered serum cysteinylglycine (3.6 versus 2.8 micromol/L; P<0.003) levels and reduced the levels of many amino acids in the liver. We also found that expression of Tg-CBS rescued the severe hyperhomocysteinemia and neonatal lethality of Cbs deletion animals. Our results show that elevating CBS activity is an effective method to lower plasma homocysteine levels. In addition, the creation of an inducible mouse system to modulate plasma homocysteine will also be useful in the study of homocysteine-related vascular disease.
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PMID:Modulation of cystathionine beta-synthase level regulates total serum homocysteine in mice. 1510 97


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